Email updates

Keep up to date with the latest news and content from BMC Medical Genetics and BioMed Central.

Open Access Highly Accessed Research article

The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project

Onofre Combarros1*, Donald R Warden2, Naomi Hammond3, Mario Cortina-Borja4, Olivia Belbin5, Michael G Lehmann2, Gordon K Wilcock6, Kristelle Brown5, Patrick G Kehoe7, Rachel Barber7, Eliecer Coto8, Victoria Alvarez8, Panos Deloukas3, Rhian Gwilliam3, Reinhard Heun109, Heike Kölsch9, Ignacio Mateo1, Abderrahim Oulhaj11, Alejandro Arias-Vásquez1213, Maaike Schuur1214, Yurii S Aulchenko12, M Arfan Ikram12, Monique M Breteler12, Cornelia M van Duijn12, Kevin Morgan5, A David Smith2 and Donald J Lehmann2

Author Affiliations

1 Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital (University of Cantabria), 39008 Santander, Spain

2 Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Physiology, Anatomy and Genetics, South Parks Road, Oxford OX1 3QX, UK

3 The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

4 Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK

5 School of Molecular Medical Sciences, Institute of Genetics, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK

6 Nuffield Department of Medicine, University of Oxford, Level 4, John Radcliffe Hospital, Oxford OX3 9DU, UK

7 Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Frenchay Hospital, Frenchay Bristol, BS16 1LE, UK

8 Genética Molecular, Hospital Central de Asturias, Oviedo, Spain

9 Department of Psychiatry, University of Bonn, Bonn, Germany

10 Royal Derby Hospital, Uttoxeter Road, Derby DE22 3NE, UK

11 OPTIMA, Nuffield Department of Medicine, University of Oxford, Level 4, John Radcliffe Hospital, Oxford OX3 9DU, UK

12 Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands

13 Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior & Department of Human Genetics, Radboud University Nijmegen, Medical Centre, P.O. Box 9101, HP 966, Nijmegen 6500 HB, The Netherlands

14 Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands

For all author emails, please log on.

BMC Medical Genetics 2010, 11:162  doi:10.1186/1471-2350-11-162


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2350/11/162


Received:4 June 2010
Accepted:11 November 2010
Published:11 November 2010

© 2010 Combarros et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine β-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls.

Methods

We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD.

Results

We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain.

Conclusions

Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Background

Noradrenergic neurones in Alzheimer's disease

The loss of noradrenergic neurones of the locus coeruleus is a striking feature of sporadic Alzheimer's disease (AD). A gradual, moderate loss is found with ageing in healthy people [1-3], but a more dramatic loss is seen in AD. A meta-analysis [4] showed similarly high losses of noradrenergic neurones (24 studies) as of cholinergic neurones (33 studies), with losses four times greater than those of dopaminergic cells in AD. Noradrenergic neurones project from the brainstem to innervate wide areas of the forebrain [5]. Levels of noradrenaline (NA, norepinephrine) in target regions have also sometimes been reported lowered in ageing [6,7], e.g. in the hippocampus and hypothalamus. They have generally been found to be further reduced in AD [8-13], e.g. in the hippocampus, hypothalamus, caudate nucleus, putamen and neocortex, although not in one small study [14]. Both the loss of noradrenergic neurones [15] and that of NA in target regions [8,13,16] have been correlated with the severity of the disease. Changes in the noradrenergic system in AD are reviewed in Hermann et al 2004 [17].

Dopamine β-hydroxylase -1021C/T

Dopamine β-hydroxylase (DBH) catalyses the conversion of dopamine to NA. Its activity is also reduced in postmortem hippocampus and neocortex in AD [18,19], without correlating with the loss of noradrenergic neurones [19]. Variation in DBH activity both in serum and in CSF has been reported to be over 80% heritable [20]. The single nucleotide polymorphism (SNP), -1021C/T (rs1611115), has been identified as the main predictor of DBH activity in plasma [21,22]. It is responsible for ~30% to ~50% of the considerable variation in such activity between people, as replicated in several different populations [21,23-27]. The -1021T allele contributes to greatly lowered DBH activity through codominant inheritance [21]. In view therefore of the chronic inflammation seen in the AD brain [28,29] and of the anti-inflammatory role of NA [30], Mateo et al 2006 [31] investigated interactions between the -1021T allele and SNPs of the regulatory regions of the pro-inflammatory cytokine genes, IL1A and IL6. They reported interactions between DBH -1021TT and both IL1A -889T (rs1800587) and IL6 -174GG (rs1800795). In the Epistasis Project, we recently confirmed [32] reported interactions between the inflammation-related cytokine genes, IL6 and IL10, that contribute to the development of AD. We therefore now decided also to examine the interactions between DBH and both IL1A and IL6 in the Epistasis Project, with 1757 cases of AD and 6294 controls. In view of the age and sex differences that have been reported in brain inflammation in the elderly [33], and of the relevant influence of sex steroids [34], we also examined possible interactions of DBH with age and sex. We found an association of the low-activity DBH -1021T allele with the risk of AD.

Methods

Study population

The Epistasis Project aims primarily to replicate interactions that have been reported to affect the risk of AD. Sample-sets were drawn from narrow geographical regions with relatively homogeneous, Caucasian populations, by seven AD research groups: Bonn, Bristol, Nottingham, OPTIMA (Oxford), Oviedo, Rotterdam and Santander. Sample characteristics by geographical region are given in Additional file 1: Table S1. All AD cases were diagnosed "definite" or "probable" by CERAD or NINCDS-ADRDA criteria. AD cases were sporadic, i.e. possible autosomal dominant cases were excluded, based on family history. The median ages (interquartile ranges) of AD cases were 79.0 (73.0-85.2) and of controls were 76.9 (71.3-83.0). Fuller details of our sample-sets are given elsewhere [32]. Ethical approval was obtained by each of the participating groups (Additional file 1: Table S2).

Additional file 1. Combarros et al 2010: The dopamine β-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.

Format: DOC Size: 72KB Download file

This file can be viewed with: Microsoft Word ViewerOpen Data

Genotyping

Blood samples were taken after written informed consent had been obtained from the subjects or their representatives. Genotyping for the six centres other than Rotterdam (below) was performed at the Wellcome Trust Sanger Institute, using the iPLEX Gold assay (Sequenom Inc.). Whole genome amplified DNA was used for 82% of samples; genomic DNA was used for the 18% of samples that were not suitable for whole genome amplification. A Sequenom iPLEX, designed for quality control purposes, was used to assess genotype concordance between genomic and whole genome amplified DNA for 168 individuals. Assays for all SNPs were designed using the eXTEND suite and MassARRAY Assay Design software version 3.1 (Sequenom Inc.). Samples were amplified in multiplexed PCR reactions before allele specific extension. Allelic discrimination was obtained by analysis with a MassARRAY Analyzer Compact mass spectrometer. Genotypes were automatically assigned and manually confirmed using MassArray TyperAnalyzer software version 4.0 (Sequenom Inc.). Gender markers were included in all iPLEX assays as a quality control metric for confirmation of plate/sample identity. Genotyping of DBH intron 10 A/G (rs1611131) and IL6 intron 2 A/G (rs2069837) was carried out using KASPar technology by KBioscience http://www.kbioscience.co.uk webcite. No SNPs were imputed.

Genotyping in the Rotterdam cohort was done on Version 3 Illumina-Infinium-II HumanHap550 SNP array (Illumina, San Diego, USA) and additionally, SNPs were imputed using MACH software http://www.sph.umich.edu/csg/abecasis/MACH/ webcite with HapMap CEU Release 22 as a reference [35]. The reliability of imputation was estimated for each imputed SNP with the ratio of expected and observed dosage variance (O/E ratio). Only samples with high-quality extracted DNA were genotyped; 5974 were available with good quality genotyping data; 5502 of these had reliable phenotypes. For this study, DBH exon 3 Ala197Thr (rs5320), IL1A exon 5 Ala114Ser (rs17561) and IL6 intron 2 A/G (rs2069837) were genotyped, and the other SNPs (Table 1) were imputed.

Table 1. Studied SNPs

Statistical analysis

We assessed associations with logistic regression models, controlling for age, gender, study centre and the ε4 allele of apolipoprotein E (APOEε4), using R Version 2.10.1 (R Foundation for Statistical Computing, Vienna, Austria). The adjusted synergy factors [36] were derived from the interaction terms in those models. Since both -1021TT and -1021TC are associated with reduced plasma DBH activity, although the former more so than the latter, we combined the two genotypes in all analyses, i.e. using a model that assumes that the -1021T allele is dominant. For reasons of power, it is usual to use minor-allele-dominant models in interaction analyses, even where a codominant model might produce a better fit. This is the almost invariable practice with the APOEε4 allele.

Heterogeneity among centres was controlled thus. We first fitted a model including random effect terms by centre, which accounts for correlated (clustered) observations within populations while avoiding estimating extra parameters in the regression models. We then fitted centre as a fixed effect term with six contrasts. We compared the goodness of fit of both approaches using Akaike's Information Criterion, which penalises the model's likelihood by a function of the number of parameters in the model. We found that the model with fixed effect terms by centre was preferable and used it to control for different frequencies between populations. Overdispersion was controlled by fitting generalized linear models with a quasi-binomial family with logit link.

Where the overall synergy factor was significant at p < 0.05, the seven individual centres and the two geographical regions, North Europe and North Spain, were also examined. In view of the genetic differences found between North and South Europe in previous studies [37-39] and in the Epistasis Project (Table 1, Additional file 1: Table S1, and [40]), we included separate analyses for North Europe and North Spain. North Europe here comprises Bonn, Bristol, Nottingham, Oxford and Rotterdam; North Spain comprises Oviedo and Santander.

Power calculations were based on the observed synergy factor values. A Cox proportional hazards model, with a frailty term to account for centre differences, controlling also for sex and APOE4, was fitted to see whether the DBH -1021T allele was associated with the onset age of AD, after confirming the assumption of proportional hazards. Comparisons of allelic frequencies between North Spain and North Europe were by Fisher's exact test. Linkage disequilibrium data were estimated using the R genetics library http://cran.r-project.org/web/packages/genetics/index.html webcite. All tests of significance and power calculations were two-sided.

Results

The data

Table 1 shows the allelic frequencies and patterns of linkage disequilibrium of the eight studied SNPs in controls. There were differences between North Europe and North Spain in allelic frequencies of five SNPs. IL1A -889C/T and exon 5 Ala114Ser were in almost 100% linkage disequilibrium. Genotype distributions of the eight SNPs in AD and controls from each of the seven centres are shown in Additional file 1: Table S3; allelic frequencies by country are given in Additional file 1: Table S4. Hardy-Weinberg analysis was performed for both cases and controls, both in the Rotterdam samples and in the samples from the other six centres, which were genotyped by the Sanger Institute. In three of these 32 analyses, the samples were not in Hardy-Weinberg equilibrium, compared with two as would be expected by chance. Those three sample-sets were all AD cases from the six centres: IL1A -889C/T (p = 0.03) and intron 6 A/C (p = 0.004), and IL6 -174G/C (p = 0.02). Since another SNP, Arg535Cys in exon 11 of DBH (rs6271), has also been reported to influence plasma DBH activity [23,24], although much less so than -1021C/T, we performed preliminary analysis of that SNP on data from six centres, i.e. excluding Rotterdam.

Associations of DBH -1021TT+TC with AD

DBH -1021TT+TC versus CC was associated with AD overall: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). There were interactions with sex and age (Table 2). The interaction with sex was significant overall and in North Europe, while that with age was significant overall and in North Spain. In view of those interactions, we stratified our analyses by age and by sex. Those stratified analyses established that the observed association of DBH -1021TT+TC with AD in the population was due to an association nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004) (Table 3). Similar results were obtained in North Europe and North Spain (Table 4). The DBH -1021T allele was not associated with onset age of AD.

Table 2. Interactions of DBH -1021TT+TC versus CC with sex and age in AD risk

Table 3. Odds ratios of AD for DBH -1021TT+TC vs CC, stratified by sex and by age

Table 4. Odds ratios of AD for DBH -1021TT+TC vs CC in certain subsets

Interactions with IL1A and IL6

We found an interaction between DBH -1021TT+TC and IL1A -889TT (Table 5): synergy factor = 1.9 (1.2-3.1, 0.005). This interaction was consistent between North Europe and North Spain. We also found a possible interaction between DBH -1021TT+TC and IL6 -174GG (Table 5), but only in North Europe: synergy factor = 1.5 (1.07-2.0, 0.02) (Table 5). We also analysed the results for DBH -1021TT+TC and IL1A -889TT when stratified by each other (Table 6). Those analyses showed that each risk factor was only associated with AD in the presence of the other factor.

Table 5. Interactions of DBH -1021TT+TC vs CC with variants of IL1A and IL6 in AD risk

Table 6. Odds ratios of AD for the DBH and IL1A variants*, when stratified by each other

Other DBH SNPs: exon 3 Ala197Thr (rs5320), intron 10 A/G (rs1611131) and exon 11 Arg535Cys (rs6271)

There were no main effects of any of these SNPs. The overall odds ratio for 197Ala homozygotes (versus carriers of one or two copies of Thr) was 1.01 (0.8-1.25, 0.9) and for intron 10 AA (versus AG+GG) was 0.97 (0.85-1.1, 0.7). However, the interaction of 197Ala homozygotes with sex was slightly stronger than that of -1021TT+TC, but only in Northern Europeans: synergy factor = 2.3 (1.4-3.9, 0.001). The only apparently significant result for intron 10 AA was an interaction with age, only in Northern Spanish, very similar to that of -1021TT+TC: synergy factor = 2.1 (1.1-3.95, 0.025). The only apparently significant result in the preliminary analysis of Arg535Cys was probably due to chance (data not shown).

Discussion

Interpretation of results

We have shown a clear association between the presence of the DBH -1021T allele and AD (Table 4): odds ratio for -1021TT+TC versus CC = 1.2 (1.06-1.4, 0.005), controlling for centre, age, sex and APOE ε4 genotype. This association was nearly restricted to men < 75 years old: 2.2 (1.4-3.3, 0.0004). The interactions with sex and age were both significant (p = 0.01 and 0.03, respectively, Table 2). Table 3 shows that the effect of age was consistent between men and women and the effect of gender was consistent between the two age groups. All these results were consistent between North Europe and North Spain (Tables 2 & 4). We therefore believe these associations to be real. However, large numbers will be needed to replicate these interactions (see the power estimates in Tables 2 & 5).

We also found a probable interaction between the presence of DBH -1021T and IL1A -889TT (Table 5), thus partially replicating Mateo et al 2006 [31], who reported an interaction between DBH -1021TT and IL1A -889T. The synergy factors were consistent between North Europe and North Spain (Table 5). Also, each risk factor, i.e. DBH -1021T and IL1A -889TT, was only associated with AD risk in the presence of the interacting factor (Table 6), thus indicating epistasis. However, although the results were consistent in the three largest sample-sets, Rotterdam, Santander and OPTIMA, models for the smaller sample-sets proved unreliable. Thus we can only describe this interaction as probable, not definite. The IL1A -889TT genotype has been found to increase transcriptional activity in assays of promoter function [41,42]. Meta-analyses [43-45] have shown heterogeneity between studies, but a possible, weak association of the -889T allele with AD: odds ratio = 1.07 (0.99-1.16) (23 Sept 2010, 29 sample-sets: http://www.alzgene.org/ webcite).

We also found a possible interaction between DBH -1021T and IL6 -174GG, partially replicating that between DBH -1021TT and IL6 -174GG reported by Mateo et al [31]. However, in this case the interaction was only seen in North Europe and the results were inconsistent between the two European regions (Table 5) and between the seven centres. Thus, this apparent interaction may not be real. The only apparently significant results for the other two DBH SNPs studied in our full dataset, exon 3 Ala197Thr (rs5320) and intron 10 A/G (rs1611131), were somewhat inconsistent, precluding any firm conclusions.

The -1021T allele has consistently been associated with strikingly reduced plasma DBH activity [21,23-27]. The allele partially disrupts consensus transcriptional motifs for n-MYC and MEF-2 [26]. When DBH promoter/reporters were cotransfected with n-MYC or MEF-2, the allele affected the response [26]. The allele is thus functional and, although we cannot assume that it has the same effect in the brain as in the plasma, we may plausibly speculate that it does also have some influence on DBH activity in the brain. DBH catalyses the conversion of dopamine to NA. The -1021C/T SNP may therefore affect levels of both catecholamines. However, although reduced levels of NA are seen in AD brain [8-13], raised levels of dopamine have generally not been found [8,12,13]. We will therefore base the discussion below on the hypothesis that the association of the -1021T allele with AD risk is mainly due to an effect on NA levels in the brain.

The control of inflammation in the brain

One likely result of changed DBH activity is misregulation of inflammation in the brain. The mechanisms that control inflammation in the brain differ from those in the periphery; an important part of the former control system is the noradrenergic network (reviewed in [30]). The anti-inflammatory role of NA has been shown in cultured cells and rodent brains (reviewed in [30]). Raised levels of NA reduced activation of astrocytes [46] and microglia [47-49], and lowered expression of pro-inflammatory cytokines [47-50] and chemokines [50]. Noradrenergic depletion increased production of pro-inflammatory cytokines [51] and chemokines [52], and activation of astrocytes [53] and microglia [51], and impaired microglial phagocytosis of β-amyloid [50]. Astrocytes are considered major targets of noradrenaline in the brain (reviewed in [54,55]), through their β2-adrenoceptors [46,54], which activate the cyclic AMP pathway [54,56], which may lead to the activation of peroxisome proliferator-activated receptors (PPARs) [56-58]. These receptors down-regulate expression of pro-inflammatory genes (PPARγ: [59]; PPARδ: [60]). The importance of the cyclic AMP pathway in AD was underlined by the recent identification of the cyclic AMP-response element-binding protein as the transcription factor of most relevance to networks of AD-related genes [61]. The inhibition of the pro-inflammatory transcription factor, nuclear factor κB, by its endogenous inhibitor, IκB, may also mediate the anti-inflammatory effects of NA [62-64]. However, the anti-inflammatory role of NA remains controversial [53] and it may even have pro-inflammatory actions in certain conditions [65-67]. Nevertheless, the predominant evidence suggests a mainly anti-inflammatory, regulatory role of NA in the brain. This role is weakened in ageing [1-3] and seriously disrupted in AD [4]. Thus, elderly non-demented carriers of the DBH -1021T allele with presumed low activity may be more vulnerable to low-grade inflammation in the brain. This effect has been reported to be stronger in elderly men < 80 years old [33], consistent with our results.

Other potential mechanisms

In cell cultures and rodent brains, brain-derived neurotrophic factor (BDNF) has been reported: to be induced by NA in astrocytes and neurones [68-71]; to exert certain neuroprotective actions (reviewed in [72]); and to promote synaptic plasticity and contribute to learning and memory (reviewed in [73]). BDNF levels have been found to be decreased in the postmortem hippocampus and neocortex [74-76] in AD. A large recent meta-analysis of the BDNF Val66Met polymorphism [77] found that the Met allele was associated with AD in women, but not men.

Noradrenergic neurones also produce and secrete other neuromodulators and neurotrophins (reviewed in [78]). These neurones also have roles in glial energy metabolism [54,55] and the maintenance of the microvasculature [79,80] and of the blood-brain barrier [81]. NA has actions against oxidative stress [57,82,83] and against excitotoxicity [84,85]. Downstream of NA, the cyclic AMP pathway has neuroprotective and antioxidant actions in neuronal cultures [86,87]. NA protects against the neurotoxicity of β-amyloid (reviewed in [88]). However, potentially pathogenic contributions of NA to AD have also been reported [65,67,89].

Conclusions

Our results support an association of the functional DBH -1021T allele with increased risk of AD in men < 75 years. Any of the above neuroprotective effects of NA (reviewed in [90]) may influence that risk and that association. However, there is considerable evidence for the role of NA in the control of inflammation in the brain (reviewed in [30]). In view therefore also of the likely interaction between DBH and the pro-inflammatory gene, IL1A, we suggest that the predominant, although not sole, mechanism of the above association with AD is misregulation of inflammation in the brain. There is substantial evidence that inflammation is an early, pre-clinical factor in the development of AD (reviewed in [91]). We have previously proposed [32] that inflammation is not only a reaction to the pathology of AD, but contributes to its onset. Our present results support that view.

Abbreviations

AD: Alzheimer's disease; APOEε4: apolipoprotein E ε4; CERAD: Consortium to Establish a Registry for Alzheimer's Disease; CI: confidence interval; CSF: cerebrospinal fluid; DBH: dopamine β-hydroxylase; DBH: the gene for DBH; IL1A: the gene for interleukin-1α; IL6: the gene for interleukin-6; NINCDS-ADRDA: National Institute of Neurological, Communicative Diseases and Stroke-Alzheimer's Disease and Related Diseases Association; OPTIMA: the Oxford Project to Investigate Memory and Ageing; SNP: single nucleotide polymorphism.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

All authors contributed to the design of the study. In addition, ADS and DJL set up the Epistasis Project, with the help of the other authors. ADS and DJL decided on the strategy of the Epistasis Project, with the help of CMvD, OC, KM, PK, RH, MC-B, DRW and EC. ADS, DJL, CMvD, OC, KM, PK, RH, MC-B, DRW and EC chose the genetic interactions to study. OC and IM produced the hypothesis for this study. KM and OB gave extensive advice on the choice of SNPs to study. DJL made the final selection of polymorphisms. HK, RB, KM, DRW, EC and IM provided DNA for genotyping. DRW gave technical advice throughout. RG and NH were responsible for the genotyping of 6 sample-sets. AA-V was responsible for the Rotterdam genotyping. MC-B and DJL decided on the analytical approach. MC-B and AO advised on statistics. DJL, MGL, MC-B and AO performed the analyses. DJL drafted the manuscript. OC submitted the manuscript and is responsible for correspondence. All authors read the manuscript, studied it critically for its intellectual content and approved the final draft.

Acknowledgements

We are most grateful to the Moulton Charitable Foundation for a grant to fund the Epistasis Project, to all those who have provided support for the individual clinical studies and to the Alzheimer's Research Trust and the Thomas Willis Oxford Brain Collection for tissue for DNA extraction. GW was partly funded by the NIHR Biomedical Research Centre Programme, Oxford. UCL Institute of Child Health receives funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Centre for Paediatric Epidemiology and Biostatistics also benefits from funding support from the Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health (G0400546). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE1 and 2), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012)

References

  1. Brody H: An examination of cerebral cortex and brainstem aging. In Neurobiology of Aging. Edited by Terry RD. Gershon S: Raven Press, New York; 1976. OpenURL

  2. Mann DMA, Yates PO, Hawkes J: The pathology of the human locus ceruleus.

    Clin Neuropathol 1983, 2:1-7. PubMed Abstract OpenURL

  3. Tomlinson BE, Irving D, Blessed G: Cell loss in the locus coeruleus in senile dementia of Alzheimer type.

    J Neurol Sci 1981, 49:419-428. PubMed Abstract | Publisher Full Text OpenURL

  4. Lyness SA, Zarow C, Chui HC: Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-analysis.

    Neurobiol Aging 2003, 24:1-23. PubMed Abstract | Publisher Full Text OpenURL

  5. Sara SJ: The locus coeruleus and noradrenergic modulation of cognition.

    Nat Rev Neurosci 2009, 10(3):211-223. PubMed Abstract | Publisher Full Text OpenURL

  6. Carlsson A, Adolfsson R, Aquilonius SM, Gottfries CG, Oreland L, Svennerholm L, Winblad B: Biogenic amines in human brain in normal aging, senile dementia, and chronic alcoholism.

    Adv Biochem Psychopharmacol 1980, 23:295-304. PubMed Abstract OpenURL

  7. Winblad B, Hardy J, Bäckman L, Nilsson LG: Memory function and brain biochemistry in normal aging and in senile dementia.

    Ann N Y Acad Sci 1985, 444:255-268. PubMed Abstract | Publisher Full Text OpenURL

  8. Adolfsson R, Gottfries CG, Roos BE, Winblad B: Changes in the brain catecholamines in patients with dementia of Alzheimer type.

    Br J Psychiatry 1979, 135:216-223. PubMed Abstract | Publisher Full Text OpenURL

  9. Francis PT, Palmer AM, Sims NR, Bowen DM, Davison AN, Esiri MM, Neary D, Snowden JS, Wilcock GK: Neurochemical studies of early-onset Alzheimer's disease. Possible influence on treatment.

    N Engl J Med 1985, 313(1):7-11. PubMed Abstract | Publisher Full Text OpenURL

  10. Gottfries CG, Adolfsson R, Aquilonius SM, Carlsson A, Eckernas SA, Nordberg A, Oreland L, Svennerholm L, Wiberg A, Winblad B: Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT).

    Neurobiol Aging 1983, 4(4):261-271. PubMed Abstract | Publisher Full Text OpenURL

  11. Hoogendijk WJG, Feenstra MGP, Botterblom MHA, Gilhuis J, Sommer IEC, Kamphorst W, Eikelenboom P, Swaab DF: Increased activity of surviving locus ceruleus neurons in Alzheimer's disease.

    Ann Neurol 1999, 45:82-91. PubMed Abstract | Publisher Full Text OpenURL

  12. Palmer AM, Wilcock GK, Esiri MM, Francis PT, Bowen DM: Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease.

    Brain Res 1987, 401(2):231-238. PubMed Abstract | Publisher Full Text OpenURL

  13. Reinikainen KJ, Soininen H, Riekkinen PJ: Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy.

    J Neurosci Res 1990, 27:576-586. PubMed Abstract | Publisher Full Text OpenURL

  14. D'Amato RJ, Zweig RM, Whitehouse PJ, Wenk GL, Singer HS, Mayeux R, Price DL, Snyder SH: Aminergic systems in Alzheimer's disease and Parkinson's disease.

    Ann Neurol 1987, 22:229-236. PubMed Abstract | Publisher Full Text OpenURL

  15. Bondareff W, Mountjoy CQ, Roth M, Rossor MN, Iversen LL, Reynolds GP, Hauser DL: Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer's disease.

    Alzheimer Dis Assoc Disord 1987, 1:256-262. PubMed Abstract | Publisher Full Text OpenURL

  16. Matthews KL, Chen CP, Esiri MM, Keene J, Minger SL, Francis PT: Noradrenergic changes, aggressive behavior, and cognition in patients with dementia.

    Biol Psychiatry 2002, 51(5):407-416. PubMed Abstract | Publisher Full Text OpenURL

  17. Herrmann N, Lanctôt KL, Khan LR: The role of norepinephrine in the behavioral and psychological symptoms of dementia.

    J Neuropsychiatry Clin Neurosci 2004, 16(3):261-276. PubMed Abstract OpenURL

  18. Cross AJ, Crow TJ, Perry EK, Perry RH, Blessed G, Tomlinson BE: Reduced dopamine-beta-hydroxylase activity in Alzheimer's disease.

    British medical journal (Clinical research ed) 1981, 282(6258):93-94. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  19. Perry EK, Tomlinson BE, Blessed G, Perry RH, Cross AJ, Crow TJ: Neuropathological and biochemical observations on the noradrenergic system in Alzheimer's disease.

    J Neurol Sci 1981, 51:279-287. PubMed Abstract | Publisher Full Text OpenURL

  20. Oxenstierna G, Edman G, Iselius L, Oreland L, Ross SB, Sedvall G: Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals--a genetic study.

    J Psychiatr Res 1986, 20(1):19-29. PubMed Abstract | Publisher Full Text OpenURL

  21. Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, Kim KS, Kim CH, Malison RT, Gelernter J, et al.: A quantitative-trait analysis of human plasma dopamine β-hydroxylase activity: evidence for a major functional polymorphism at the DBH locus.

    Am J Hum Genet 2001, 68:515-522. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  22. Zabetian CP, Buxbaum SG, Elston RC, Köhnke MD, Anderson GM, Gelernter J, Cubells JF: The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine β-hydroxylase activity.

    Am J Hum Genet 2003, 72:1389-1400. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  23. Tang YL, Epstein MP, Anderson GM, Zabetian CP, Cubells JF: Genotypic and haplotypic associations of the DBH gene with plasma dopamine beta-hydroxylase activity in African Americans.

    Eur J Hum Genet 2007, 15(8):878-883. PubMed Abstract | Publisher Full Text OpenURL

  24. Tang Y, Anderson GM, Zabetian CP, Kohnke MD, Cubells JF: Haplotype-controlled analysis of the association of a non-synonymous single nucleotide polymorphism at DBH (+ 1603C --> T) with plasma dopamine beta-hydroxylase activity.

    Am J Med Genet B Neuropsychiatr Genet 2005, 139B(1):88-90. PubMed Abstract | Publisher Full Text OpenURL

  25. Köhnke MD, Zabetian CP, Anderson GM, Kolb W, Gaertner I, Buchkremer G, Vonthein R, Schick S, Lutz U, Köhnke AM, et al.: A genotype-controlled analysis of plasma dopamine beta-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function.

    Biol Psychiatry 2002, 52(12):1151-1158. PubMed Abstract | Publisher Full Text OpenURL

  26. Chen Y, Wen G, Rao F, Zhang K, Wang L, Rodriguez-Flores JL, Sanchez AP, Mahata M, Taupenot L, Sun P, et al.: Human dopamine beta-hydroxylase (DBH) regulatory polymorphism that influences enzymatic activity, autonomic function, and blood pressure.

    J Hypertens 2010, 28:76-86. PubMed Abstract | Publisher Full Text OpenURL

  27. Bhaduri N, Mukhopadhyay K: Correlation of plasma dopamine β-hydroxylase activity with polymorphisms in DBH gene: a study on Eastern Indian population.

    Cell Mol Neurobiol 2008, 28(3):343-350. PubMed Abstract | Publisher Full Text OpenURL

  28. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, et al.: Inflammation and Alzheimer's disease.

    Neurobiol Aging 2000, 21:383-421. PubMed Abstract | Publisher Full Text OpenURL

  29. Rogers J, Webster S, Lue L-F, Brachova L, Civin WH, Emmerling M, Shivers B, Walker D, McGeer P: Inflammation and Alzheimer's disease pathogenesis.

    Neurobiol Aging 1996, 17:681-686. PubMed Abstract | Publisher Full Text OpenURL

  30. Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E: Noradrenergic regulation of inflammatory gene expression in brain.

    Neurochem Int 2002, 41:357-365. PubMed Abstract | Publisher Full Text OpenURL

  31. Mateo I, Infante J, Rodríguez E, Berciano J, Combarros O, Llorca J: Interaction between dopamine β-hydroxylase and interleukin genes increases Alzheimer's disease risk.

    J Neurol Neurosurg Psychiatry 2006, 77:278-279. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  32. Combarros O, van Duijn CM, Hammond N, Belbin O, Arias-Vásquez A, Cortina-Borja M, Lehmann MG, Aulchenko YS, Schuur M, Kölsch H, et al.: Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease.

    J Neuroinflammation 2009, 6:22. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  33. Overmyer M, Helisalmi S, Soininen H, Laakso M, Riekkinen PS, Alafuzoff I: Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue.

    Acta Neuropathol (Berl) 1999, 97:383-392. Publisher Full Text OpenURL

  34. Kipp M, Beyer C: Impact of sex steroids on neuroinflammatory processes and experimental multiple sclerosis.

    Front Neuroendocrinol 2009, 30(2):188-200. PubMed Abstract | Publisher Full Text OpenURL

  35. Ikram MA, Seshadri S, Bis JC, Fornage M, DeStefano AL, Aulchenko YS, Debette S, Lumley T, Folsom AR, van den Herik EG, et al.: Genomewide association studies of stroke.

    N Engl J Med 2009, 360:1718-1728. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  36. Cortina-Borja M, Smith AD, Combarros O, Lehmann DJ: The synergy factor: a statistic to measure interactions in complex diseases.

    BMC Res Notes 2009, 2(1):105. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  37. Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KJH: Geography of HFE C282Y and H63D mutations.

    Genet Test 2000, 4:183-198. PubMed Abstract | Publisher Full Text OpenURL

  38. Lehmann DJ, Cortina-Borja M, Warden DR, Smith AD, Sleegers K, Prince JA, van Duijn CM, Kehoe PG: Large meta-analysis establishes the ACE insertion-deletion polymorphism as a marker of Alzheimer's disease.

    Am J Epidemiol 2005, 162:305-317. PubMed Abstract | Publisher Full Text OpenURL

  39. Capurso C, Solfrizzi V, D'Introno A, Colacicco AM, Capurso SA, Mastroianni F, Liaci M, Vendemiale G, Capurso A, Panza F: The cathepsin D gene exon 2 (C224T) polymorphism and sporadic Alzheimer's disease in European populations.

    J Gerontol A Biol Sci Med Sci 2005, 60(8):991-996. PubMed Abstract OpenURL

  40. Lehmann DJ, Schuur M, Warden DR, Hammond N, Belbin O, Kölsch H, Lehmann MG, Wilcock GK, Brown K, Kehoe PG, et al.: Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project.

    Neurobiol Aging 2010.

    Epub ahead of print

    PubMed Abstract | Publisher Full Text OpenURL

  41. Dominici R, Cattaneo M, Malferrari G, Archi D, Mariani C, Grimaldi LME, Biunno I: Cloning and functional analysis of the allelic polymorphism in the transcription regulatory region of interleukin-1a.

    Immunogenetics 2002, 54:82-86. PubMed Abstract | Publisher Full Text OpenURL

  42. Wei X, Chen X, Fontanilla C, Zhao L, Liang Z, Dodel R, Hampel H, Farlow M, Du Y: C/T conversion alters interleukin-1A promoter function in a human astrocyte cell line.

    Life Sci 2007, 80:1152-1156. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  43. Rainero I, Bo M, Ferrero M, Valfrè W, Vaula G, Pinessi L: Association betwen the interleukin-1a gene and Alzheimer's disease: a meta-analysis.

    Neurobiol Aging 2004, 25:1293-1298. PubMed Abstract | Publisher Full Text OpenURL

  44. Combarros O, Llorca J, Sánchez-Guerra M, Infante J, Berciano J: Age-dependent association between interleukin-1A (-889) genetic polymorphism and sporadic Alzheimer's disease. A meta-analysis.

    J Neurol 2003, 250:987-989. PubMed Abstract | Publisher Full Text OpenURL

  45. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE: Systematic meta-analyses of Alzheimer disease genetic association studies: the Alzgene database.

    Nature Genetics 2007, 39:17-23.

    Accessed on 23 Sept, 2010

    PubMed Abstract | Publisher Full Text OpenURL

  46. Frohman EM, Vayuvegula B, Gupta S, van den Noort S: Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (Ia) antigen expression on cultured astrocytes via beta-2-adrenergic signal transduction mechanisms.

    Proc Natl Acad Sci USA 1988, 85(4):1292-1296. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  47. Dello Russo C, Boullerne AI, Gavrilyuk V, Feinstein DL: Inhibition of microglial inflammatory responses by norepinephrine: effects on nitric oxide and interleukin-1beta production.

    J Neuroinflammation 2004, 1(1):9. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  48. Mori K, Ozaki E, Zhang B, Yang L, Yokoyama A, Takeda I, Maeda N, Sakanaka M, Tanaka J: Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors.

    Neuropharmacology 2002, 43(6):1026-1034. PubMed Abstract | Publisher Full Text OpenURL

  49. O'Sullivan JB, Ryan KM, Curtin NM, Harkin A, Connor TJ: Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration.

    Int J Neuropsychopharmacol 2009, 12(5):687-699. PubMed Abstract | Publisher Full Text OpenURL

  50. Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, et al.: Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine.

    Proc Natl Acad Sci USA 2010, 107(13):6058-6063. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  51. Heneka MT, Galea E, Gavriluyk V, Dumitrescu-Ozimek L, Daeschner J, O'Banion MK, Weinberg G, Klockgether T, Feinstein DL: Noradrenergic depletion potentiates β-amyloid-induced cortical inflammation: implications for Alzheimer's disease.

    J Neurosci 2002, 22:2434-2442. PubMed Abstract | Publisher Full Text OpenURL

  52. Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Dyrks T, Thiele A, Heneka MT: Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits.

    Neurochem Int 2010, 57(4):375-382. PubMed Abstract | Publisher Full Text OpenURL

  53. Wenk GL, McGann K, Hauss-Wegrzyniak B, Rosi S: The toxicity of tumor necrosis factor-alpha upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer's disease.

    Neuroscience 2003, 121(3):719-729. PubMed Abstract | Publisher Full Text OpenURL

  54. Laureys G, Clinckers R, Gerlo S, Spooren A, Wilczak N, Kooijman R, Smolders I, Michotte Y, De Keyser J: Astrocytic beta(2)-adrenergic receptors: From physiology to pathology.

    Prog Neurobiol 2010. PubMed Abstract | Publisher Full Text OpenURL

  55. Stone EA, Ariano MA: Are glial cells targets of the central noradrenergic system? A review of the evidence.

    Brain Res Brain Res Rev 1989, 14(4):297-309. PubMed Abstract | Publisher Full Text OpenURL

  56. Klotz L, Sastre M, Kreutz A, Gavrilyuk V, Klockgether T, Feinstein DL, Heneka MT: Noradrenaline induces expression of peroxisome proliferator activated receptor γ (PPAR γ) in murine primary astrocytes and neurons.

    J Neurochem 2003, 86:907-916. PubMed Abstract | Publisher Full Text OpenURL

  57. Madrigal JL, Kalinin S, Richardson JC, Feinstein DL: Neuroprotective actions of noradrenaline: effects on glutathione synthesis and activation of peroxisome proliferator activated receptor delta.

    J Neurochem 2007, 103(5):2092-2101. PubMed Abstract | Publisher Full Text OpenURL

  58. Michael LF, Lazar MA, Mendelson CR: Peroxisome proliferator-activated receptor gamma1 expression is induced during cyclic adenosine monophosphate-stimulated differentiation of alveolar type II pneumonocytes.

    Endocrinology 1997, 138(9):3695-3703. PubMed Abstract | Publisher Full Text OpenURL

  59. Szanto A, Nagy L: The many faces of PPARgamma: anti-inflammatory by any means?

    Immunobiology 2008, 213(9-10):789-803. PubMed Abstract | Publisher Full Text OpenURL

  60. Bishop-Bailey D, Bystrom J: Emerging roles of peroxisome proliferator-activated receptor-beta/delta in inflammation.

    Pharmacol Ther 2009, 124(2):141-150. PubMed Abstract | Publisher Full Text OpenURL

  61. Satoh J, Tabunoki H, Arima K: Molecular network analysis suggests aberrant CREB-mediated gene regulation in the Alzheimer disease hippocampus.

    Dis Markers 2009, 27(5):239-252. PubMed Abstract | Publisher Full Text OpenURL

  62. Farmer P, Pugin J: Beta-adrenergic agonists exert their "anti-inflammatory" effects in monocytic cells through the IkappaB/NF-kappaB pathway.

    Am J Physiol Lung Cell Mol Physiol 2000, 279(4):L675-682. PubMed Abstract | Publisher Full Text OpenURL

  63. Gavrilyuk V, Dello Russo C, Heneka MT, Pelligrino D, Weinberg G, Feinstein DL: Norepinephrine increases I kappa B alpha expression in astrocytes.

    J Biol Chem 2002, 277(33):29662-29668. PubMed Abstract | Publisher Full Text OpenURL

  64. Heneka MT, Gavrilyuk V, Landreth GE, O'Banion MK, Weinberg G, Feinstein DL: Noradrenergic depletion increases inflammatory responses in brain: effects on IκB and HSP70 expression.

    J Neurochem 2003, 85:387-398. PubMed Abstract | Publisher Full Text OpenURL

  65. Norris JG, Benveniste EN: Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine.

    J Neuroimmunol 1993, 45(1-2):137-145. PubMed Abstract | Publisher Full Text OpenURL

  66. Schlachetzki JC, Fiebich BL, Haake E, de Oliveira AC, Candelario-Jalil E, Heneka MT, Hüll M: Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia.

    J Neuroinflammation 2010, 7:2. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  67. Tomozawa Y, Yabuuchi K, Inoue T, Satoh M: Participation of cAMP and cAMP-dependent protein kinase in beta-adrenoceptor-mediated interleukin-1 beta mRNA induction in cultured microglia.

    Neurosci Res 1995, 22(4):399-409. PubMed Abstract | Publisher Full Text OpenURL

  68. Juric DM, Miklic S, Carman-Krzan M: Monoaminergic neuronal activity up-regulates BDNF synthesis in cultured neonatal rat astrocytes.

    Brain Res 2006, 1108(1):54-62. PubMed Abstract | Publisher Full Text OpenURL

  69. Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA: Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant.

    Pharmacol Biochem Behav 2003, 75(1):81-88. PubMed Abstract | Publisher Full Text OpenURL

  70. Cirelli C, Tononi G: Differential expression of plasticity-related genes in waking and sleep and their regulation by the noradrenergic system.

    J Neurosci 2000, 20(24):9187-9194. PubMed Abstract | Publisher Full Text OpenURL

  71. Chen MJ, Nguyen TV, Pike CJ, Russo-Neustadt AA: Norepinephrine induces BDNF and activates the PI-3K and MAPK cascades in embryonic hippocampal neurons.

    Cell Signal 2007, 19(1):114-128. PubMed Abstract | Publisher Full Text OpenURL

  72. Murer MG, Yan Q, Raisman-Vozari R: Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease.

    Prog Neurobiol 2001, 63:71-124. PubMed Abstract | Publisher Full Text OpenURL

  73. Bekinschtein P, Cammarota M, Izquierdo I, Medina JH: BDNF and memory formation and storage.

    Neuroscientist 2008, 14(2):147-156. PubMed Abstract | Publisher Full Text OpenURL

  74. Hock C, Heese K, Hulette C, Rosenberg C, Otten U: Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas.

    Arch Neurol 2000, 57(6):846-851. PubMed Abstract | Publisher Full Text OpenURL

  75. Narisawa-Saito M, Wakabayashi K, Tsuji S, Takahashi H, Nawa H: Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer's disease.

    Neuroreport 1996, 7(18):2925-2928. PubMed Abstract | Publisher Full Text OpenURL

  76. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW: BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease.

    Neuron 1991, 7(5):695-702. PubMed Abstract | Publisher Full Text OpenURL

  77. Fukumoto N, Fujii T, Combarros O, Kamboh MI, Tsai SJ, Matsushita S, Nacmias B, Comings DE, Arboleda H, Ingelsson M, et al.: Sexually dimorphic effect of the Val66Met polymorphism of BDNF on susceptibility to Alzheimer's disease: New data and meta-analysis.

    Am J Med Genet B Neuropsychiatr Genet 2010, 153B:235-242. PubMed Abstract | Publisher Full Text OpenURL

  78. Weinshenker D: Functional consequences of locus coeruleus degeneration in Alzheimer's disease.

    Curr Alzheimer Res 2008, 5(3):342-345. PubMed Abstract | Publisher Full Text OpenURL

  79. Cohen Z, Molinatti G, Hamel E: Astroglial and vascular interactions of noradrenaline terminals in the rat cerebral cortex.

    J Cereb Blood Flow Metab 1997, 17(8):894-904. PubMed Abstract | Publisher Full Text OpenURL

  80. Scheibel AB, Duong TH, Tomiyasu U: Denervation microangiopathy in senile dementia, Alzheimer type.

    Alzheimer Dis Assoc Disord 1987, 1(1):19-37. PubMed Abstract | Publisher Full Text OpenURL

  81. Kalinin S, Feinstein DL, Xu HL, Huesa G, Pelligrino DA, Galea E: Degeneration of noradrenergic fibres from the locus coeruleus causes tight-junction disorganisation in the rat brain.

    Eur J Neurosci 2006, 24(12):3393-3400. PubMed Abstract | Publisher Full Text OpenURL

  82. Traver S, Salthun-Lassalle B, Marien M, Hirsch EC, Colpaert F, Michel PP: The neurotransmitter noradrenaline rescues septal cholinergic neurons in culture from degeneration caused by low-level oxidative stress.

    Mol Pharmacol 2005, 67:1882-1891. PubMed Abstract | Publisher Full Text OpenURL

  83. Troadec JD, Marien M, Darios F, Hartmann A, Ruberg M, Colpaert F, Michel PP: Noradrenaline provides long-term protection to dopaminergic neurons by reducing oxidative stress.

    J Neurochem 2001, 79(1):200-210. PubMed Abstract | Publisher Full Text OpenURL

  84. Madrigal JL, Leza JC, Polak P, Kalinin S, Feinstein DL: Astrocyte-derived MCP-1 mediates neuroprotective effects of noradrenaline.

    J Neurosci 2009, 29(1):263-267. PubMed Abstract | Publisher Full Text OpenURL

  85. Xiao Z, Deng PY, Rojanathammanee L, Yang C, Grisanti L, Permpoonputtana K, Weinshenker D, Doze VA, Porter JE, Lei S: Noradrenergic depression of neuronal excitability in the entorhinal cortex via activation of TREK-2 K+ channels.

    J Biol Chem 2009, 284(16):10980-10991. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  86. Echeverria V, Clerman A, Dore S: Stimulation of PGE receptors EP2 and EP4 protects cultured neurons against oxidative stress and cell death following beta-amyloid exposure.

    Eur J Neurosci 2005, 22(9):2199-2206. PubMed Abstract | Publisher Full Text OpenURL

  87. Koriyama Y, Chiba K, Mohri T: Propentofylline protects beta-amyloid protein-induced apoptosis in cultured rat hippocampal neurons.

    Eur J Pharmacol 2003, 458(3):235-241. PubMed Abstract | Publisher Full Text OpenURL

  88. Counts SE, Mufson EJ: Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity.

    J Neurochem 2010, 113(3):649-660. PubMed Abstract | Publisher Full Text OpenURL

  89. Sun L, Wang X, Liu S, Wang Q, Wang J, Bennecib M, Gong CX, Sengupta A, Grundke-Iqbal I, Iqbal K: Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat.

    FEBS Lett 2005, 579(1):251-258. PubMed Abstract | Publisher Full Text OpenURL

  90. Marien MR, Colpaert FC, Rosenquist AC: Noradrenergic mechanisms in neurodegenerative diseases: a theory.

    Brain Res Rev 2004, 45:38-78. PubMed Abstract | Publisher Full Text OpenURL

  91. Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA: Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer's disease.

    Neurodegener Dis 2010, 7(1-3):38-41. PubMed Abstract | Publisher Full Text OpenURL

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2350/11/162/prepub